Project Summary/Abstract The goal of this SBIR is to develop a novel drug, IpY, to improve advanced ER/PR+, Her2- breast cancer outcomes. Almost 250,000 US women will be diagnosed this year, and over 40,000 will die, suggesting that despite advances in treatments, breast cancer remains a significant health burden. ER/PR+, Her2- tumors occur in approximately 40% of breast cancer patients, are associated with poor survival, and are candidates for estrogen pathway targeting drugs, such as Letrozole, but clinical outcomes for this patient population are still inadequate: Roughly half of treated ER/PR+ patients will develop metastatic disease within 5 y. CDK4 targeting drugs (CDK4i), like Palbociclib, were recently approved in combination with Letrozole or Fulvestrant as a frontline therapy for metastatic ER/PR+, Her2- patients. However, even these therapies do not represent ?cure?. While combined ER and CDK4 inhibition treatment significantly extends Progression Free Survival (PFS), those treated eventually develop resistance to the combination and the Overall Survival (OS) of these patients is unchanged, suggesting that drug resistance remains an unmet need. Resistance develops because of compensation by another protein, CDK2, suggesting that to be effective, therapies must be developed to inhibit BOTH CDK4 and CDK2. The drug, IpY, is a novel peptide-lipid formulation, which targets a different protein, p27Kip1, that in turn causes inhibition of both CDK4 and CDK2, and represents the first therapeutic that would accomplish this. IpY reduces proliferation in breast cancer tissue culture models and in vivo, prevents drug resistance in animal models. IpY is innovative because 1) the p27 target is unique, so blocking it results in a specific treatment with fewer off-target effects, resulting in less toxicity, 2) IpY targets acquired drug resistance by hitting both CDK4 and CDK2 at the onset, resulting in a prolonged response to the drug, which should increase patient survival and 3) IpY can be used alone or in combination with Palbociclib, to make this already improved therapy better. The hypothesis to be tested in this SBIR project is that IpY can be delivered efficiently and with limited toxicity in vivo following systemic IV administration to clinically relevant mouse models, thereby demonstrating the feasibility of using this novel liposomal peptide nanoparticle approach in more advanced pre-clinical studies. Specifically, this SBIR will 1) demonstrate that IpY reduces tumor progression and increases OS in genetically engineered models (GEM) that develops breast cancer in an immunocompetent background, and 2) Demonstrate that IpY has a stable blood half-life and is delivered to tumors in different models. In Phase II, Concarlo will utilize CROs for the IND-enabling pharmacokinetics/ADME (absorption, distribution, metabolism, excretion) and Good Laboratory Practice (GLP)-compliant toxicology studies. Sales of Palbociclib were $1 billion in Q1 2019, but resistant patients had no additional therapeutic options. Concarlo is generating a CDK4/6/2 and NOT CDK1 inhibitor to deal with the resistance seen in these patients. As such there is no current competition for IpY. !